During the past four decades, survival rates and cure for childhood cancer have improved dramatically. Previously a nearly uniformly fatal disease when not amenable to surgical management alone, cancer is now curable in the majority of children. This improvement is a direct result of the collaborative efforts of clinical and laboratory investigators in the context of cooperative, multi-center clinical trials. Further significant improvements in overall survival have been recently attained in some specific pediatric cancers. However, improvement has not been observed in all diagnostic types of childhood cancer. Recognizing the need to accelerate progress despite the difficulties encountered with limited patient numbers and constrained resources, the Children's Oncology Group (COG) successfully elected to unify its efforts to develop a coordinated and robust research agenda without sacrificing the progress that had resulted from previous competitive strategies in specific disease areas. Major refinements in risk classification based on expanded understanding of disease and host biology in larger numbers of patients have resulted from these efforts. Refinements in the definition of risk groups and increasing subgroups of patients and rare cancer types necessitate even more cooperation. Therapeutic intensification from augmentation of conventional agents and schedule modification is unlikely to result in further improvement, providing a compelling justification and emergent need to enhance correlative biologic investigation and accelerate the process of identification and validation of molecular targets in specific pediatric cancers. Moreover, incremental progress requires that pediatric cancer clinical investigation fully exploit evolving developments in molecular cancer therapeutics in a more rapid drug development paradigm than heretofore utilized for childhood cancer, especially for those types resistant to conventional therapies; this is also required to reduce the potential for significant acute and long-term sequelae associated with current therapy. In order to achieve its mission to cure and prevent childhood cancer, the COG will design and conduct clinical trials that will continue to define evidence-based care standards, conduct laboratory investigations into cancer biology and variability in host response to treatment and translate these findings into new, more effective and less toxic treatments. We will identify causes of childhood cancer and develop strategies aimed at cancer prevention. Finally, we will evaluate therapeutic interventions with a goal of improving the quality of life and survivorship in infant, children, adolescents and young adults with cancer.